The wide availability, low cost, and multiple biochemical, molecular and hemodynamic effects of[unreadable] hyperoxia make it ideally suited as a neuroprotective strategy. In animal studies, and in a recent pilot human[unreadable] study, we have documented that breathing high-flow oxygen (normobaric hyperoxia therapy or NBO) during[unreadable] brain ischemia confers potent neuroprotection. The benefit of NBO appears to be transient, similar to that[unreadable] observed in prior hyperbaric oxygen studies. However, sustained benefit does occur if NBO-treated tissue is[unreadable] reperfused. We believe that today, with enhanced reperfusion rates from newer therapies such as tPA, and[unreadable] advances in MRI that allow serial assessment of tissue ischemia-reperfusion, there exists an exciting[unreadable] opportunity to assess whether NBO's transient tissue-salvaging effects can be converted (via induced or[unreadable] spontaneous reperfusion) into sustained benefit. By preventing early ischemic cell death, NBO may be a[unreadable] feasible strategy to extend the narrow time window for IV tissue plasminogen activator (tPA) therapy.[unreadable] In this proposal we aim to extend our preliminary work in a double-blind study enrolling 150 acute (<12[unreadable] hours) ischemic stroke patients over 5 years. Patients will receive NBO or Room Air for 8 hours and will[unreadable] undergo serial clinical examinations and diffusion-perfusion MRI (DWI/PWI). Safety and efficacy of NBO will[unreadable] be determined in an 'intention to treat' statistical analysis of change in NIH stroke scale scores during and[unreadable] after therapy. The potential synergistic benefit of NBO with reperfusion will be assessed. We will also[unreadable] compare MRI ischemic lesion growth and hemorrhage rates, and perform novel voxel-based analyses of[unreadable] DWI and PWI parameters. In year 1 we will exclude tPA-treated patients and investigate the safety of NBO[unreadable] with tPA in an embolic (clot-based) rodent stroke model. If the combination appears safe in rodents, and if[unreadable] the year 1 human data raises no safety concerns, we will expand to include tPA-treated patients. Finally, we[unreadable] will conduct pathological and in-vivo MRI studies in rodent stroke models to investigate whether NBO can[unreadable] extend the tPA time window, and to investigate NBO's effects on cerebral hemodynamics.[unreadable] These studies are significant because they will comprehensively test the effects of oxygen in the ischemic[unreadable] brain. Breathing high-flow oxygen may prove to be a simple, practical, portable, and potentially cost-effective[unreadable] therapy that improves stroke outcomes, either independently or by extending the time window for IV tPA.